Relevance: Cognitive deficits are the most common adverse consequence observed in children with Fetal Alcohol Spectrum Disorder (FASD). Currently, there are no effective pharmacotherapeutic interventions for learning disabilities associated with FASD. However, there are a growing number of therapeutic agents in various stages of preclincial development and clinical trials for treating cognitive deficits associated with a variety of neurologic and psychiatric illnesses. To our knowledge, there have been no systematic investigations to discern whether such agents could provide some benefit for treating the cognitive deficits of patients with FASD. We submit that an important first step towards addressing this question is to determine whether a preclincial investigation of cognition-enhancing agents could provide the pharmacologic rationale for subsequent clinical studies of promising agents in patients with FASD. Project Summary: The objective of this new research project is to investigate whether cognition-enhancing agents are effective in reversing fetal ethanol-induced deficits in hippocampal synaptic plasticity and learning using a rat model of moderate prenatal ethanol exposure. Within the time and budgetary constraints of this Developmental Project funding mechanism, we will limit this initial "proof of concept" investigation to an assessment of the effects of a single cognition enhancing agent on the performance of fetal ethanol-exposed offspring in two behavioral paradigms sensitive to moderate prenatal ethanol exposure. Subsequently, we will examine the effects of this agent on two measures of hippocampal synaptic plasticity, the physiologic mechanisms thought to subserve learning, which are also sensitive to moderate prenatal ethanol exposure. The working hypothesis for this project is that the cognition-enhancing histamine H3 receptor antagonist ABT-239 will diminish fetal ethanol-induced learning deficits by enhancing hippocampal synaptic plasticity in fetal ethanol-exposed offspring. We will examine the effects of five different doses of ABT-239 on fetal ethanol-induced deficits in contextual fear-conditioned learning (Aim 1A) and spatial navigation deficits in the Morris Water Task (Aim 1B). Then, we will conduct dose-response studies of the effects of ABT-239 on fetal ethanol-induced deficits in long-term potentiation in vivo (Aim 2A) and activity-dependent potentiation of electrically evoked amino acid release (Aim 2B) in the dentate gyrus of dorsal hippocampal formation. Based on our hypothesis, we predict that ABT-239 will improve performance on the learning tasks in a manner that corresponds to improvements in one or both measures of hippocampal synaptic plasticity. The long-term objectives of this research program are to determine whether this experimental approach can provide the pharmacologic rationale for initiating clinical trials of such agents for treating cognitive deficits associated with FASD and whether this rodent model of moderate prenatal ethanol exposure has utility for assessing the therapeutic potential of a variety of cognition-enhancing agents.